Disorders of the renal and urogenital system represent a major health burden, remain poorly understood, and are often clinically intractable. Of equal importance, anatomical defects in these organs are associated frequently with serious, life-threatening systemic syndromes that can remain refractive to diagnosis. The mission of our Center is to bring together cutting-edge genomics tools and interpretative biological assays to potentiate and accelerate the molecular diagnosis of these disorders. We propose three major activities: a) to phenotype, recruit and biobank samples from families recruited at the Duke clinics but also referred to us from across the United States with congenital anatomical renal and urogenital defects that have failed to secure a molecular diagnosis through traditional means; b) to perform exome (and ultimately genome) sequencing on appropriate family members; c) to functionally test a subset of discovered variation that is of predicted clinical value and to develop in vitro (primary cells) and in vivo tools (zebrafish and mouse) to model the effects of such variation; d) to synthesize hybrid clinical and research data that, in collaboration with the clinical management team, can inform future management and intervention in patients. In parallel, we propose two high-risk pilot activities aimed at improving both the genetics and the discovery of novel therapeutic leads. First, we will develop the technology for the rapid identification of new zebrafish renal mutants that can accelerate the identification of new genes important in kidney development. Second, we will generate new platforms for the screening of lead compounds in zebrafish models of renal disease (both previously established and newly-developed as part of our Center). Finally, because our Center represents a collaboration between patients, physicians and basic scientists, we will develop information platforms to facilitate the dissemination of exome-wide research and clinical data to both physicians and patient families, and to learn iteratively from this community about how to best implement such information to improve health care. Taken together, our Center will provide a much-needed niche in the field, will likely improve the knowledge base of both physicians and patients about syndromes with a renal and urogenital component, and will provide the foundation for accelerated diagnosis, management and treatment.